Osteoporosis is a common clinical condition characterized by low bone mass that increases the risk of fragility fractures in the elderly population. Since bone formation is clearly impaired in osteoporotic patients, a more complete understanding of the fundamental molecular mechanisms that regulate bone formation is likely to lead to the development of novel therapies. However, the only FDA approved anabolic therapy is PTH, which has limited efficacy. Therefore, identification of novel molecular pathways which influence bone formation is crucial to the development of compounds to combat osteoporosis. We have identified the nuclear transcription factor Ror as a novel player in the regulation of bone mass. Ror expression decreases during osteoblast differentiation and increases in the bone marrow-derived osteoprogenitor pool during aging. In contrast, overexpression of Ror inhibits osteoblast differentiation. Deletion of Ror in mice results in significant increases in bone mass throughout aging, due to an increase in bone formation with a concomitant decrease in bone resorption. We have also found that Ror represses the Runx2 and Wnt pathways, two important pathways that positively influence bone formation. Collectively, these data establish Ror as a novel and important transcription factor in the regulation of bone homeostasis. We propose to further explore the mechanism of Ror action with particular emphasis on regulation of both Runx2 and Wnt activities. In Aim 1 we will definitively establish the role of osteoprogenitor-derived Ror in aging bone. We hypothesize that specific deletion of Ror in osteoprogenitors will preserve bone mass during aging and that inducible deletion of Ror in aged, osteoporotic mice will inhibit, or even reverse, bone loss. In Aim 2 we will investigate the role of Ror in the inhibition of Runx2 activity in osteoprogenitors We have developed a novel technique to isolate and study highly enriched osteoprogenitor cells from mouse bone marrow without the need for in vitro culture. We will also examine the role of a novel set of Ror-regulated miRNAs in the control of Runx2 activity. In Aim 3, we will examine the role of Ror in the inhibition of Wnt activity. We hypothesize that loss of Ror increases Wn activity and results in an expansion of the osteoprogenitor cell pool. Furthermore, we have evidence that Ror also represses Opg, a negative regulator of osteoclastogenesis, which will be tested in this proposal. Therefore, functional characterization of the role of Ror as a novel regulator of bone mass will advance our understanding the fundamental processes underlying the control of bone homeostasis, and provide important information for the development of Ror-specific inhibitors as an anabolic osteoporosis therapy.